PROJECT SUMMARY Cancer-cachexia (CC), loss in muscle mass that cannot be fully reversed through nutritional intervention, is understudied relative to other muscle pathologies, affects up to 80% of patients and is responsible for 20-40% of cancer-related deaths. Unfortunately, therapeutic approaches to prevent CC lack efficacy. We recently demonstrated muscle metabolic health, specifically degeneration and dysfunction of the mitochondrial network, is compromised well before muscle loss in Lewis Lung Carcinoma-induced (LLC) CC. Specifically, we observed enhanced mitochondrial reactive oxygen species (ROS) emission and depressed Opa1 protein 1 wk following tumor implant with subsequent degeneration of the mitochondrial network at 2 wks, and impaired respiratory function and induction of mitophagy protein BNIP3 at 3 wks with muscle loss at 4 wks. Our preliminary evidence suggests attenuation of CC is possible by targeting mitochondrial quality (e.g., Opa1 activation, BNIP-3, mitochondrial antioxidants). These data provide novel insight to potential mechanisms that may be targeted to prevent onset of CC and highlight the need for preventive measures. The overarching goal of our laboratory and this proposal is to utilize characterization of key steps in development of CC to identify mechanisms and efficacious therapeutic approaches. However, many questions remain: 1) Does this course of events persist across models of cachexia? 2) How does the tumor-bearing state interact with chemotherapy on CC? 3) Can we specifically target pre-wasting effects to prevent CC? 4) Can we specifically deliver drugs to muscle to prevent CC? To answer these questions, we will pursue the following aims (Fig 1): Aim 1. Define development of cancer-induced muscle wasting across additional pre-clinical models and in conjunction with chemotherapy. Aim 2. Determine if nodal points identified in development of CC may be targeted to prevent or attenuate muscle wasting. Aim 3. Determine if mitochondria-targeted or muscle-specific delivery of therapeutics prevents CC.